Clinical application of molecular therapeutics targeting signaling molecules holds tremendous promise for the management of patients with cancer. Within the cell, signals are routed through specific signal transduction pathways, many of which can interact to form networks. Targeting a node or molecule within this network can be challenging since signals can bypass the inhibition and continue to propagate. One of the challenges in the use of targeted therapeutics to inhibit cancer cell proliferation is to understand how signal flows through the network and what combination of molecules have to be blocked in order to effectively inhibit proliferation. My long-term goal is to understand the systems function of signaling networks in cancer and utilize this knowledge to develop and implement novel approaches to patient management. The objectives of this application are to determine the regulators of the EGFR signaling network in breast cancer to identify optimal combinations of targets for therapy, and to determine how differences in activity of regulatory molecules and homeostatic loops alters response to targeted therapies. We will integrate existing proteomic and computational modeling technology to address these important issues in the use of combination targeted therapy for cancer. Aim 1. Determine rational approaches to targeting the EGFR signaling network in lapatinib resistant breast cancer cells. Aim 2. Determine approaches to target regulatory molecules defining EGFR/AKT/MAPK network function in human breast cancer cells. Aim 3. Determine the response to rational combinatorial targeted therapy of the EGFR/MAPK/AKT network on cell proliferation and tumor growth. These aims will be addressed using a systems biology approach using experimental data from cell lines, functional proteomics and xenograft tumors in mice, integrated with computational modeling of the signaling network. PUBLIC HEALTH RELEVANCE: The treatment and management of patients with cancer is entering a new and very exciting era. New drugs that target specific proteins are showing tremendous promise if they are given to the right patients. In this proposal we will determine what combinations of these new drugs work best for different tumors based on the aberrations within the cancer cells. With the idea being that different tumors will need a different combination of drugs and in the future we can give specific combinations of drugs to different individuals. [unreadable] [unreadable] [unreadable]